Acute myocardial infarction (AMI) is one of the leading causes of death and disability. The dysregulation of cardiac endothelial cells plays a significant role in the pathogenesis of AMI. In the present study, we investigated the potential of memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist used in the treatment of Alzheimer’s disease, to mitigate the effects of ischemia-reperfusion injury in the peripheral vasculature using human umbilical cord endothelial cells (HUVECs). Previous studies have identified anti-inflammatory and antioxidant effects of memantine, but the effects of memantine on angiogenesis and microtubule formation have not been fully elucidated. Our findings indicate that pretreatment with memantine significantly reduced the expression of interleukin (IL)-6 and IL-8, which are both serum markers if AMI severity. We also demonstrate that memantine could prevent mitochondrial dysfunction and oxidative stress by rescuing mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS) by NADPH oxidase-4 (NOX-4). Importantly, memantine also promoted the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant signaling pathway. Importantly, memantine pretreatment improved cell viability and prevented the decrease in microtubule formation induced by OGD/R. Through a phosphoinositide-3-kinase (PI3K) inhibition experiment, we determined that the PI3K/protein kinase B (Akt) pathway is essential for the effects of memantine on angiogenesis. Together, our findings suggest a potential role for memantine in the prevention and treatment of AMI.